ES2563211T5 - Procedure for the preparation of aminocrotonyl compounds - Google Patents
Procedure for the preparation of aminocrotonyl compounds Download PDFInfo
- Publication number
- ES2563211T5 ES2563211T5 ES12155662T ES12155662T ES2563211T5 ES 2563211 T5 ES2563211 T5 ES 2563211T5 ES 12155662 T ES12155662 T ES 12155662T ES 12155662 T ES12155662 T ES 12155662T ES 2563211 T5 ES2563211 T5 ES 2563211T5
- Authority
- ES
- Spain
- Prior art keywords
- amino
- chloro
- fluorophenyl
- tetrahydrofuran
- yloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
DESCRIPCIÓNDESCRIPTION
Procedimiento para la preparación de compuestos de aminocrotoniloProcedure for the preparation of aminocrotonyl compounds
La invención se refiere a un procedimiento mejorado para la preparación de dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazo¡ina, así como a dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1 -oxo-2-buten-1 -il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina y a su uso para la preparación de medicamentos.The invention relates to an improved process for the preparation of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene dimaleate -1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoin, and 4-[(3-chloro-4-fluorophenyl)amino]-6-{[ dimaleate 4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline and its use for the preparation of medicines.
4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina posee la siguiente estructura:4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S) -tetrahydrofuran-3-yloxy)-quinazoline has the following structure:
y es ya conocida por el documento WO 02/50043 en el que se describen compuestos con valiosas propiedades farmacológicas a las que pertenece, en particular, un efecto inhibidor sobre la transducción de señales inducida por tirosina-quinasas y un efecto inhibidor sobre la transducción de señales inducida por el receptor del factor de crecimiento epidermal (EGF-R). Por lo tanto, compuestos de este tipo son adecuados para el tratamiento de enfermedades, en particular para el tratamiento de enfermedades tumorales, de enfermedades de los pulmones y de las vías respiratorias y de enfermedades del tracto gastrointestinal y de los conductos biliares y de la vesícula biliar. En el documento WO 02/50043 se da a conocer un procedimiento de preparación, en el que se preparan compuestos de aminocrotonilo (IV) tal como, por ejemplo, 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazo¡ina en una reacción en un solo recipiente a partir del correspondiente eslabón de anilina (II), ácido bromocrotónico (III), cloruro de oxalilo y una amina secundaria (véase el Esquema 1).and it is already known from document WO 02/50043 which describes compounds with valuable pharmacological properties to which it belongs, in particular, an inhibitory effect on the signal transduction induced by tyrosine kinases and an inhibitory effect on the transduction of signals induced by the epidermal growth factor receptor (EGF-R). Compounds of this type are therefore suitable for the treatment of diseases, in particular for the treatment of tumor diseases, of diseases of the lungs and of the respiratory tract and of diseases of the gastrointestinal tract and of the bile and gallbladder ducts. bile. WO 02/50043 discloses a preparation process, in which aminocrotonyl(IV) compounds such as, for example, 4-[(3-chloro-4-fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin in a single reaction vessel from the corresponding aniline linkage (II), bromocrotonic acid (III), oxalyl chloride and a secondary amine (see Scheme 1).
Esquema 1:Scheme 1:
En el caso de este procedimiento, el rendimiento ascendió a como máximo 50%. Además, la purificación se realizó, por norma general, mediante cromatografía en columna. Por lo tanto, el procedimiento no era adecuado para la preparación a escala técnica de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina. Además, el método tenía el inconveniente de que el ácido bromocrotónico no era comercialmente adquirible en grandes cantidades, y también el correspondiente éster metílico de ácido bromocrotónico sólo podía estar disponible en una pureza de aproximadamente el 80%. Estas circunstancias se oponen asimismo a la idoneidad de este procedimiento para la preparación técnica de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1 -il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina.In the case of this process, the yield was at most 50%. In addition, the purification was carried out, as a rule, by means of column chromatography. Therefore, the procedure was not suitable for the technical scale preparation of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7 -((S)-tetrahydrofuran-3-yloxy)-quinazoline. In addition, the method had the drawback that bromocrotonic acid was not commercially available in large quantities, and also the corresponding bromocrotonic acid methyl ester could only be available in a purity of about 80%. These circumstances also preclude the suitability of this procedure for the technical preparation of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2 -buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline.
A la vista de los inconvenientes antes descritos del procedimiento de preparación conocido, es misión de la presente invención poner a disposición un procedimiento que permita la preparación de dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1 -oxo-2-buten-1 -il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina, con empleo de materiales de partida fácilmente accesibles en una elevada pureza y sin una gran complejidad técnica. Este nuevo procedimiento debe ser adecuado también para la síntesis a escala técnica y, por consiguiente, para la aplicación comercial.In view of the above-described drawbacks of the known preparation process, it is the object of the present invention to provide a process that makes it possible to prepare 4-[(3-chloro-4-fluorophenyl)amino]-6-{ dimaleate [4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, using readily available starting materials in high purity and without great technical complexity. This new procedure should also be suitable for synthesis on a technical scale and therefore for commercial application.
Este problema se resuelve mediante el procedimiento de acuerdo con la invención. Junto a la capacidad de realización técnica con elevados rendimientos, otras ventajas de la vía de síntesis de acuerdo con la invención son muy buenas purezas químicas y un bajo contenido en cis, inferior a 0,1%.This problem is solved by the method according to the invention. In addition to the ability to perform technically with high yields, other advantages of the synthesis route according to the invention are very good chemical purities and a low cis content, less than 0.1%.
Conforme al procedimiento de acuerdo con la invención, el correspondiente compuesto de aminoarilo (V) se hace reaccionar con un ácido di-(alquil C1-4)-fosfonoacético, preferiblemente con ácido dietilfosfonoacético, en disolventes adecuados, después de la correspondiente activación, preferiblemente con 1,1 -carbonildiimidazol, 1,1 -carbonilditriazol o anhídrido de ácido propanofosfónico, de manera particularmente preferida con 1,1 -carbonildiimidazol, de acuerdo con el Esquema 2. Como disolventes pueden utilizarse, por ejemplo, tetrahidrofurano (THF), dimetilformamida (DMF) o acetato de etilo.According to the process according to the invention, the corresponding aminoaryl compound (V) is reacted with a di-(C1-4 alkyl)-phosphonoacetic acid, preferably with diethylphosphonoacetic acid, in suitable solvents, after corresponding activation, preferably with 1,1-carbonyldiimidazole, 1,1-carbonylditriazole or propanephosphonic anhydride, particularly preferably with 1,1-carbonyldiimidazole, according to Scheme 2. As solvents it is possible to use, for example, tetrahydrofuran (THF), dimethylformamide (DMF) or ethyl acetate.
La activación puede realizarse según todas las posibilidades habituales para el enlace amida es decir, por ejemplo, con 1,1-carbonildiimidazol, 1,1-carbonilditriazol, DCC (N,N-diciclohexilcarbodiimida), EDC (N'-(dimetilaminopropil)-N-etilcarbodiimida), TBTU (tetrafluoroborato de O-(benzotriazol-1-il)-N,N,N',N'-tetrametiluronio, tiazolidin-2-tionas, o por transformación en el correspondiente cloruro de ácido, por ejemplo con ayuda de cloruro de tionilo. Eventualmente, la activación se lleva a cabo con empleo de bases orgánicas tales como trietilamina o piridina, pudiéndose añadir adicionalmente DMAP (dimetilaminopiridina). Como disolventes entran en consideración DMF, THF, acetato de etilo, tolueno, hidrocarburos clorados o sus mezclas.Activation can be carried out according to all the usual possibilities for the amide bond, that is to say, for example, with 1,1-carbonyldiimidazole, 1,1-carbonylditriazole, DCC (N,N-dicyclohexylcarbodiimide), EDC (N'-(dimethylaminopropyl)- N-ethylcarbodiimide), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, thiazolidine-2-thiones, or by conversion to the corresponding acid chloride, for example with aid of thionyl chloride. If necessary, activation is carried out using organic bases such as triethylamine or pyridine, it being possible to add additionally DMAP (dimethylaminopyridine). Suitable solvents are DMF, THF, ethyl acetate, toluene, chlorinated hydrocarbons or their mixtures.
En las siguientes fórmulas, significan:In the following formulas, they mean:
X un átomo de nitrógeno,X a nitrogen atom,
Ra un grupo 3-cloro-4-fluorofenilo yRa a 3-chloro-4-fluorophenyl group and
R1 un grupo etilo.R1 an ethyl group.
Esquema 2:Scheme 2:
a) Ácido di-(alquil C1-4)-fosfonoacético, agente de activacióna) Di-(C 1-4 alkyl)-phosphonoacetic acid, activating agent
La arilamida (VI), obtenida de esta forma con un elevado rendimiento y elevada pureza, se hace reaccionar con el correspondiente 2-aminoacetaldehído con el empleo de bases orgánicas o inorgánicas adecuadas en el sentido de una reacción de Wittig-Horner-Emmons (Esquema 3). Esta reacción puede efectuarse directamente o después del aislamiento del compuesto (VI), por ejemplo por precipitación mediante la adición de, por ejemplo, terc.-butilmetiléter. A las bases adecuadas pertenecen, por ejemplo, DBU (1,5-diazabiciclo[4.3.0]non-5-eno), hidróxido de sodio e hidróxido de potasio, siendo preferidos hidróxido de sodio e hidróxido de potasio, siendo particularmente preferido hidróxido de potasio. En lugar del aldehído también se puede utilizar un correspondiente equivalente, p. ej., un hidrato o acetal, del que se libera el aldehído (de antemano o in situ). The arylamide (VI) obtained in this way in high yield and high purity is reacted with the corresponding 2-aminoacetaldehyde using suitable organic or inorganic bases in the sense of a Wittig-Horner-Emmons reaction (Scheme 3). This reaction can be carried out directly or after isolation of compound (VI), for example by precipitation by addition of, for example, tert-butyl methyl ether. Suitable bases include, for example, DBU (1,5-diazabicyclo[4.3.0]non-5-ene), sodium hydroxide and potassium hydroxide, sodium hydroxide and potassium hydroxide being preferred, hydroxide being particularly preferred. of potassium. Instead of the aldehyde, a corresponding equivalent can also be used, e.g. eg, a hydrate or acetal, from which the aldehyde is released (beforehand or in situ).
Esquema 3:Scheme 3:
b) Aldehido, base, THF/aguab) Aldehyde, base, THF/water
Como acetales se pueden emplear, por ejemplo, compuestos del siguiente tipo general:As acetals it is possible to use, for example, compounds of the following general type:
en los quein which
R3 y R4 significan en cada caso un grupo metilo yR3 and R4 each represent a methyl group and
R2 y R5 significan en cada caso un grupo etilo.R2 and R5 each denote an ethyl group.
La 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1 -il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina de la fórmula (I) se puede transformar a continuación, según el Esquema 4, en su sal dimaleato de la fórmula estructural (Ia). Para ello, el compuesto (I) se disuelve en un disolvente adecuado tal como, por ejemplo, metanol, isopropanol, n-butanol o etanol, eventualmente bajo la adición de agua, preferiblemente etanol y, bajo calentamiento, se mezcla con ácido maleico cristalino o una disolución de ácido maleico. En el caso de utilizar etanol como disolvente se trabaja preferiblemente a una temperatura entre 60 y 75 °C utilizando disolución etanólica de anhídrido maleico. Las condiciones de reacción se eligen preferiblemente de manera que la sal deseada se separa por cristalización lo más rápidamente posible. Preferiblemente, se utilizan aprox. 2 equivalentes de ácido maleico. Después de iniciada la cristalización, se enfria hasta la temperatura ambiente, se continúa agitando y se separa el cristalizado consistente en el compuesto (Ia).4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1 -yl]amino}-7-((S )-tetrahydrofuran-3-yloxy)-quinazoline of formula (I) can then be transformed, according to Scheme 4, into its dimaleate salt of structural formula (Ia). To do this, compound (I) is dissolved in a suitable solvent such as, for example, methanol, isopropanol, n-butanol or ethanol, optionally with the addition of water, preferably ethanol, and mixed with crystalline maleic acid under heating. or a solution of maleic acid. In the case of using ethanol as a solvent, preferably work at a temperature between 60 and 75 °C using ethanolic maleic anhydride solution. The reaction conditions are preferably chosen such that the desired salt crystallizes out as quickly as possible. Preferably, approx. 2 equivalents of maleic acid. After the start of crystallization, it is cooled to room temperature, stirring is continued and the crystallisate consisting of compound (Ia) is separated.
Esquema 4:Scheme 4:
c) Acido maleico, etanolc) Maleic acid, ethanol
El compuesto de partida de la fórmula (V) puede prepararse, por ejemplo, como sigue, según procedimientos en si conocidos por la bibliografia:The starting compound of the formula (V) can be prepared, for example, as follows, according to processes known per se from the literature:
Para la preparación del compuesto (V) con X = N se procede como sigue: To prepare compound (V) with X = N, proceed as follows:
Partiendo de ácido 4-cloro-antranílico (VIII; X’ = Cl) adquirible en el comercio se obtiene, por reacción con acetato de formamidina, la quinazolinona (IX) que, a continuación, se nitra utilizando ácido sulfúrico y ácido nítrico concentrado (Esquema 5b). Alternativamente, también se puede partir de ácido 4-fluoro-antranílico.Starting from commercially available 4-chloro-anthranilic acid (VIII; X' = Cl), quinazolinone (IX) is obtained by reaction with formamidine acetate, which is then nitrated using sulfuric acid and concentrated nitric acid ( Scheme 5b). Alternatively, it is also possible to start with 4-fluoro-anthranilic acid.
Esquema 5b:Scheme 5b:
a: X’ = Cla: X' = Cl
b: X’ = Fb: X' = F
d) acetato de formamididinad) formamididine acetate
e) H2SO4 , HNO3 conc.e) H 2 SO 4 , HNO 3 conc.
El regioisómero (X) deseado de los productos de nitración, así obtenidos, se clora luego y el producto de cloración (XI) se hace reaccionar in situ con la correspondiente amina (Esquema 6).The desired regioisomer (X) of the nitration products thus obtained is then chlorinated and the chlorination product (XI) is reacted in situ with the corresponding amine (Scheme 6).
Esquema 6:Scheme 6:
f) SOCl2, acetonitrilof) SOCl2, acetonitrile
g) RaNH2g) RaNH2
El compuesto de la fórmula (XII), así obtenido, se hace reaccionar con (S)-(+)-3-hidroxitetrahidrofurano para dar el compuesto (XIII). La hidrogenación del compuesto (XIII) o bien del compuesto (XVIII) del Esquema 5a proporciona entonces el compuesto de partida (V) (Esquema 7).The compound of the formula (XII) thus obtained is reacted with (S)-(+)-3-hydroxytetrahydrofuran to give the compound (XIII). Hydrogenation of either compound (XIII) or compound (XVIII) of Scheme 5a then provides starting compound (V) (Scheme 7).
Esquema 7:Scheme 7:
h) (S)-(+)-3-hidroxi-tetrahidrofuranoh) (S)-(+)-3-hydroxy-tetrahydrofuran
i) H2 i) H2
Otro objeto de la invención es el dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina según la reivindicación 4. Esta sal es particularmente adecuada para uso farmacéutico, dado que existe una modificación cristalina que es anhidra y muy estable.Another object of the invention is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl] dimaleate amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline according to claim 4. This salt is particularly suitable for pharmaceutical use, since there is a crystalline modification which is anhydrous and very stable.
Para la aplicación farmacéutica, un principio activo no sólo tiene que mostrar el efecto deseado, sino que, además, debe satisfacer todavía otros requisitos con el fin de poder acceder a su empleo como medicamento. Estos parámetros están ligados, en una gran parte, con la naturaleza físico-química del principio activo.For pharmaceutical application, an active principle not only has to show the desired effect, but also has to satisfy still other requirements in order to qualify for its use as a medicine. These parameters are linked, to a large extent, with the physical-chemical nature of the active ingredient.
Sin limitación a los mismos, ejemplos de estos parámetros son la estabilidad de acción de la sustancia de partida bajo diferentes condiciones del entorno, la estabilidad en el transcurso de la preparación de la formulación farmacéutica, así como la estabilidad en las composiciones finales del medicamento. El principio activo medicamentoso utilizado para la preparación de las composiciones medicamentosas debería, por lo tanto, presentar una elevada estabilidad que debe garantizarse también bajo diferentes condiciones del entorno. Esto es forzosamente necesario, con el fin de impedir que encuentren uso composiciones medicamentosas en las que, junto al principio activo real, estén contenidos, por ejemplo, productos de degradación del mismo. En uno de estos casos, un contenido en principio activo que se encuentra en formulaciones farmacéuticas podría ser más bajo que el especificado.Without limitation thereto, examples of these parameters are the stability of action of the starting substance under different environmental conditions, the stability in the course of the preparation of the pharmaceutical formulation, as well as the stability in the final compositions of the medicament. The active drug principle used for the preparation of the drug compositions should therefore have a high level of stability, which must also be guaranteed under different environmental conditions. This is necessarily necessary, in order to prevent medicinal compositions from finding use in which, together with the actual active principle, are contained, for example, degradation products thereof. In one of these cases, a content of active ingredient found in pharmaceutical formulations could be lower than specified.
La absorción de humedad reduce el contenido en principio activo debido al aumento de peso provocado por la absorción de agua. Medicamentos que tienden a la absorción de la humedad deben ser protegidos frente a ésta durante el almacenamiento, por ejemplo mediante la adición de agentes de secado adecuados o mediante almacenamiento del medicamento en un entorno protegido frente a la humead. Además, la absorción de la humedad puede reducir el contenido de principio activo medicamentoso durante la preparación, cuando el medicamento esté expuesto al entorno sin una protección de todo tipo frente a la humedad. Preferiblemente, un principio activo medicamentoso debería ser, por lo tanto, higroscópico sólo en pequeña medida.Moisture absorption reduces the active ingredient content due to weight gain caused by water absorption. Drugs that tend to absorb moisture must be protected against moisture during storage, for example by adding suitable drying agents or by storing the drug in a moisture-protected environment. In addition, the absorption of moisture can reduce the content of drug active ingredient during preparation, when the drug is exposed to the environment without any type of protection against moisture. Preferably, a medicinal active ingredient should therefore only be hygroscopic to a small extent.
Dado que es importante la modificación cristalina de un principio activo para el contenido reproducible en principio activo de una forma de administración, existe la necesidad de dilucidar de la mejor manera posible un polimorfismo eventualmente existente de un principio activo que se presenta de forma cristalina. En la medida en que se manifiesten diferentes modificaciones polimorfas de un principio activo, debería garantizarse que la modificación cristalina de la sustancia no varíe en la posterior preparación del medicamento. En caso contrario, esto podría afectar negativamente a la actividad reproducible del medicamento. Ante estos antecedentes, se prefieren principios activos que se caractericen sólo por un bajo polimorfismo.Since the crystalline modification of an active substance is important for the reproducible active substance content of an administration form, there is a need to elucidate in the best possible way possible existing polymorphisms of an active substance present in crystalline form. Insofar as different polymorphic modifications of an active substance occur, it should be ensured that the crystalline modification of the substance does not change in the subsequent preparation of the medicinal product. Otherwise, this could adversely affect the reproducible activity of the drug. Against this background, active ingredients characterized only by low polymorphism are preferred.
Otro criterio que es de extraordinaria importancia bajo determinadas circunstancias en función de la elección de la formulación o en función de la elección del procedimiento de preparación, es la solubilidad del principio activo. Si se proporcionan, por ejemplo, disoluciones de medicamentos (por ejemplo para infusiones), entonces es irrenunciable una solubilidad suficiente del principio activo en disolventes fisiológicamente compatibles. También una solubilidad suficiente del principio activo es de gran importancia para medicamentos a aplicar por vía oral.Another criterion that is of extraordinary importance under certain circumstances depending on the choice of the formulation or depending on the choice of the preparation process, is the solubility of the active principle. If, for example, drug solutions (for infusions, for example) are provided, then a sufficient solubility of the active substance in physiologically compatible solvents is essential. A sufficient solubility of the active substance is also of great importance for medicaments to be applied orally.
La presente invención tiene por misión proporcionar un principio activo medicamentoso, el cual no se caracterice sólo por una elevada actividad farmacológica, sino que, además, satisfaga de la mejor manera posible los requisitos físico-químicos precedentemente mencionados.The purpose of the present invention is to provide an active drug principle, which is not only characterized by high pharmacological activity, but also satisfies in the best possible way the previously mentioned physicochemical requirements.
Este problema se resuelve mediante dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten-1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina disuelto según la reivindicación 4.This problem is solved by 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino} dimaleate -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dissolved according to claim 4.
Dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1 -oxo-2-buten-1 -il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina posee un punto de fusión de 1782C (véase el termoanálisis reproducido en la Figura 2). El dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1 -oxo-2-buten-1 -il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina cristalino se examinó con mayor detalle mediante difracción de rayos X de polvo. El diagrama obtenido está representado en la Figura 1. La siguiente Tabla recoge los datos obtenidos en este análisis: Tabla: Reflexiones de rayos X de polvo e intensidades (normalizadas del dimaleato de dimaleato de 4-[(3-cloro-4-fluorofenil)amino]-6-{[4-(N,N-dimetilamino)-1-oxo-2-buten 1-il]amino}-7-((S)-tetrahidrofuran-3-iloxi)-quinazolina4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((( S)-tetrahydrofuran-3-yloxy)-quinazoline has a melting point of 1782C (see the thermoanalysis reproduced in Figure 2). 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-( dimaleate Crystalline (S)-tetrahydrofuran-3-yloxy)-quinazoline was examined in further detail by X-ray powder diffraction. The diagram obtained is represented in Figure 1. The following Table collects the data obtained in this analysis: Table: X-ray reflections of dust and intensities (normalized for 4-[(3-chloro-4-fluorophenyl) dimaleate dimaleate amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten 1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline
En la Tabla que antecede, el valor “2 0 [°]” representa el ángulo de difracción en grados y el valor “dhki [Á]” representa las distancias determinadas en Á entre los planos reticulares.In the above Table, the value "2 0 [°]" represents the diffraction angle in degrees and the value "d hki [Á]" represents the distances determined in Á between the lattice planes.
Los diagramas de rayos X de polvo se registraron en el marco de la presente invención mediante un difractómetro Bruker Advanced D8 equipado con un detector PSD y un ánodo de Cu como fuente de rayos X (radiación CuKa , A = 1,5418 Á, 40 kV, 40 mA).Dust X-ray patterns were recorded within the scope of the present invention using a Bruker Advanced D8 diffractometer equipped with a PSD detector and a Cu anode as X-ray source (CuK a radiation, A = 1.5418 Á, 40 kV, 40mA).
Los siguientes Ejemplos han de explicar más detalladamente la invención:The following Examples are to further explain the invention:
Ejemplos:Examples:
Ejemplo 1:Example 1:
Éster dietílico del ácido |[4-(3-cloro-4-fluoro-fenilamino)-7-((S)-tetrahidrofuran-3-iloxi)-quinazolin-6-ilcarbamoil]-metil}-fosfónico |[4-(3-Chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonic acid diethyl ester
3,58 g de 1,1-carbonildiimidazol (22,16 mol) se disponen en 12,8 litros de tetrahidrofurano y, a 40°C, se mezclan con 4,52 kg (22,16 mol) de ácido dietilfosfonoacético, disueltos en 6,5 litros de tetrahidrofurano. Se continúa agitando durante 30 minutos a 40°C. La disolución, así obtenida, se designa disolución A.3.58 g of 1,1-carbonyldiimidazole (22.16 mol) are placed in 12.8 liters of tetrahydrofuran and, at 40°C, mixed with 4.52 kg (22.16 mol) of diethylphosphonoacetic acid, dissolved in 6.5 liters of tetrahydrofuran. Stirring is continued for 30 minutes at 40°C. The solution thus obtained is called solution A.
6,39 kg (17,05 mol) de N4-(3-cloro-4-fluoro-fenil)-7-(tetrahidrofuran-3-iloxi)quinazolin-4,6-diamina se disponen en 26,5 litros de tetrahidrofurano y, a 40°C, se mezclan con la disolución A y se continúan agitando durante 2 horas a 30°C. A la suspensión se añaden 64 litros de terc.-butilmetiléter y, después del enfriamiento hasta 20°C, el precipitado se separa por centrifugación. Se lava con una mezcla a base de 16 litros de tetrahidrofurano y 16 litros de terc.-butilmetil-éter y, a continuación, con 32 litros de agua y se seca a 50°C.6.39 kg (17.05 mol) of N4-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)quinazolin-4,6-diamine are placed in 26.5 liters of tetrahydrofuran and, at 40°C, they are mixed with solution A and stirring is continued for 2 hours at 30°C. 64 liters of tert.-butyl methyl ether are added to the suspension and, after cooling to 20°C, the precipitate is separated by centrifugation. It is washed with a mixture of 16 liters of tetrahydrofuran and 16 liters of tert-butylmethyl ether and then with 32 liters of water and dried at 50°C.
Rendimiento: 6,58 kg (69,8%) de cristales blancos, contenido: HPLC 99,1 FI%Yield: 6.58 kg (69.8%) of white crystals, content: HPLC 99.1 FI%
Ejemplo 2Example 2
[4-(3-cloro-4-fluoro-fenilamino)-7-((S)-tetrahidrofuran-3-iloxi)-quinazolin-6-il]-amida de ácido (E)-4-dimetilamino-but-2-enoicoAcid (E)-4-dimethylamino-but-2 [4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl]-amide -enoic
A 4,4 litros de agua se añaden 5,6 litros de ácido clorhídrico al 30% (53,17 mol). A continuación, se añaden gota a gota 4,28 kg de (dimetilamino)-acetaldehído-dietilacetal al 95% (26,59 mol) a 30°C en el espacio de 20 minutos. La disolución de reacción se continúa agitando durante 8 horas a 35°C, se enfría hasta 5°C y se almacena bajo argón. Esta disolución se designa disolución B.To 4.4 liters of water are added 5.6 liters of 30% hydrochloric acid (53.17 mol). Then, 4.28 kg of 95% (dimethylamino)-acetaldehyde-diethylacetal (26.59 mol) are added dropwise at 30°C within 20 minutes. The reaction solution is stirred for 8 hours at 35°C, cooled to 5°C and stored under argon. This solution is designated solution B.
4,55 kg (68,06 mol) de hidróxido de potasio se disuelven en 23,5 litros de agua y se enfrían hasta -5°C. La disolución se designa disolución C.4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 liters of water and cooled to -5°C. The solution is designated solution C.
5,88 kg (10,63 mol) de éster dietílico de ácido ((4-(3-cloro-4-fluoro-fenilamino)-7-(tetrahidrofuran-3-iloxi)-quinazolin-6-ilcarbamoil)-metil)-fosfónico y 0,45 kg de cloruro de litio (10,63 mol) se disponen en 23,5 litros de tetrahidrofurano y se enfrían hasta -7°C. La disolución C fría se añade en el espacio de 10 minutos. A continuación, la disolución B se añade a -7°C en el espacio de 1 hora. Después de continuar agitando durante una hora a -5°C, la mezcla de reacción se calienta hasta 20°C y se combina con 15 litros de agua. Después del enfriamiento hasta 3°C, la suspensión se filtra con succión, el precipitado se lava con agua y se seca. Rendimiento: 5,21 kg de 100% bruto. Contenido en agua: 6,7%.5.88 kg (10.63 mol) of diethyl ester of acid ((4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl)-methyl) -phosphonic acid and 0.45 kg of lithium chloride (10.63 mol) are placed in 23.5 liters of tetrahydrofuran and cooled to -7°C. Cold solution C is added within 10 minutes. Solution B is then added at -7°C within 1 hour. After continuing to stir for one hour at -5°C, the reaction mixture is heated to 20°C and 15 liters of water are added. After cooling to 3°C, the suspension is filtered off with suction, the precipitate is washed with water and dried. Yield: 5.21 kg of 100% crude. Water content: 6.7%.
La cristalización del producto bruto se efectúa con acetato de butilo/metilciclohexano. Rendimiento: 78%, pureza HPLC 99,4% FI, contenido en agua 5,4%.The crude product is crystallized with butyl acetate/methylcyclohexane. Yield: 78%, HPLC purity 99.4% FI, water content 5.4%.
Ejemplo 3Example 3
Dimaleato de (4-(3-cloro-4-fluoro-fenilamino)-7-((S)-tetrahidrofuran-3-iloxi)-quinazolin-6-il)-amida del ácido (E)-4-dimetilamino-but-2-enoico (E)-4-Dimethylamino-but acid (4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amide dimaleate -2-enoic
6,0 kg (12,35 mol) de dimaleato de (4-(3-cloro-4-fluoro-fenilamino)-7-((S)-tetrahidrofuran-3-iloxi)-quinazolin-6-il)-amida del ácido (E)-4-dimetilamino-but-2-enoico se disponen en 84 litros de etanol y se calientan hasta 70°C y se mezclan con una disolución de 2,94 kg (25,31 mol) de ácido maleico en 36 litros de etanol. Después de iniciada la cristalización, se enfría primeramente hasta 20°C y se continúa agitando durante 2 horas, y luego durante 3 horas a 0°C. El precipitado se filtra con succión, se continúa lavando con 19 litros de etanol y se seca en vacío a 40°C. Rendimiento: 8,11 kg (91,5%)6.0 kg (12.35 mol) of (4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl)-amide dimaleate of (E)-4-dimethylamino-but-2-enoic acid are placed in 84 liters of ethanol and heated to 70°C and mixed with a solution of 2.94 kg (25.31 mol) of maleic acid in 36 liters of ethanol. After crystallization has started, it is cooled first to 20°C and stirring is continued for 2 hours, and then for 3 hours at 0°C. The precipitate is filtered off with suction, washing is continued with 19 liters of ethanol and dried in vacuo at 40°C. Yield: 8.11 kg (91.5%)
P. f.; 178°CP.f.; 178°C
1H-RMN (CD3OD): 5 = 2,47 2,27 (m+m, 2H), 2,96 (s, 6H), 4,03 (m, 2H), 4,07+3,92 (m+m, 2H), 4,18+4,03 (m+m, 2H), 5,32 (m, 1H), 6,26 (s, 4H), 6,80 (m, 1H), 6,99 (m, 1H), 7,27 (s, 1H), 7,30 (t, 1H), 7,66 (m, 1H), 7,96 (dd, 1H), 8,62 (s, 1H), 9,07 (s, 1H) ppm. 1H-NMR (CD 3 OD): 5 = 2.47 2.27 (m+m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 4.07+3.92 (m+m, 2H), 4.18+4.03 (m+m, 2H), 5.32 (m, 1H), 6.26 (s, 4H), 6.80 (m, 1H), 6.99 (m, 1H), 7.27 (s, 1H), 7.30 (t, 1H), 7.66 (m, 1H), 7.96 (dd, 1H), 8.62 (s , 1H), 9.07 (s, 1H) ppm.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10349113A DE10349113A1 (en) | 2003-10-17 | 2003-10-17 | Process for the preparation of aminocrotonyl compounds |
| DE10349113 | 2003-10-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2563211T3 ES2563211T3 (en) | 2016-03-11 |
| ES2563211T5 true ES2563211T5 (en) | 2022-12-27 |
Family
ID=34428508
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04765927.1T Active ES2440466T3 (en) | 2003-10-17 | 2004-10-12 | Procedure for the preparation of aminocrotonyl compounds |
| ES12155662T Active ES2563211T5 (en) | 2003-10-17 | 2004-10-12 | Procedure for the preparation of aminocrotonyl compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04765927.1T Active ES2440466T3 (en) | 2003-10-17 | 2004-10-12 | Procedure for the preparation of aminocrotonyl compounds |
Country Status (35)
| Country | Link |
|---|---|
| US (2) | US20050085495A1 (en) |
| EP (2) | EP2508521B2 (en) |
| JP (2) | JP4594317B2 (en) |
| KR (2) | KR101282812B1 (en) |
| CN (2) | CN1867564B (en) |
| AR (1) | AR046118A1 (en) |
| AU (2) | AU2004281938B2 (en) |
| BR (2) | BR122013033343B8 (en) |
| CA (2) | CA2759063C (en) |
| CY (2) | CY1114866T1 (en) |
| DE (1) | DE10349113A1 (en) |
| DK (2) | DK1678165T3 (en) |
| EA (1) | EA016624B1 (en) |
| EC (1) | ECSP066509A (en) |
| ES (2) | ES2440466T3 (en) |
| HK (1) | HK1095817A1 (en) |
| HR (2) | HRP20160246T4 (en) |
| HU (1) | HUE028254T2 (en) |
| IL (2) | IL174951A (en) |
| ME (1) | ME00341B (en) |
| MX (2) | MX338920B (en) |
| MY (2) | MY155425A (en) |
| NO (2) | NO333971B1 (en) |
| NZ (2) | NZ547154A (en) |
| PE (2) | PE20050965A1 (en) |
| PL (2) | PL1678165T3 (en) |
| PT (2) | PT1678165E (en) |
| RS (3) | RS53398B (en) |
| SG (1) | SG139743A1 (en) |
| SI (2) | SI1678165T1 (en) |
| TW (2) | TWI348468B (en) |
| UA (2) | UA91006C2 (en) |
| UY (2) | UY28559A1 (en) |
| WO (1) | WO2005037824A2 (en) |
| ZA (1) | ZA200602234B (en) |
Families Citing this family (83)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU90901A (en) | 1999-06-21 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh. & Co.Kg. | Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof |
| US7019012B2 (en) * | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
| DE10221018A1 (en) * | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Use of inhibitors of EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy |
| US20050043233A1 (en) * | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
| DE10349113A1 (en) * | 2003-10-17 | 2005-05-12 | Boehringer Ingelheim Pharma | Process for the preparation of aminocrotonyl compounds |
| KR100832594B1 (en) * | 2005-11-08 | 2008-05-27 | 한미약품 주식회사 | Quinazoline derivatives as an multiplex inhibitor and method for the preparation thereof |
| SI1948180T1 (en) | 2005-11-11 | 2013-06-28 | Boehringer Ingelheim International Gmbh | Combination treatment of cancer comprising egfr/her2 inhibitors |
| CA2833706C (en) | 2005-11-11 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Quinazoline derivatives for the treatment of cancer diseases |
| JP5241513B2 (en) * | 2006-01-26 | 2013-07-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Method for the synthesis of aminocrotonylamino substituted quinazoline derivatives |
| MX2009002710A (en) | 2006-09-18 | 2009-03-25 | Boehringer Ingelheim Int | Method for treating cancer harboring egfr mutations. |
| UY31867A (en) * | 2008-06-06 | 2010-01-29 | Boehringer Ingelheim Int | NEW SOLID PHARMACEUTICAL FORMULATIONS THAT INCLUDE BIBW 2992 |
| EP2387401A1 (en) | 2009-01-14 | 2011-11-23 | Boehringer Ingelheim International GmbH | Method for treating colorectal cancer |
| MX2011009034A (en) | 2009-03-11 | 2011-09-22 | Auckland Uniservices Ltd | Prodrug forms of kinase inhibitors and their use in therapy. |
| US20120142703A1 (en) | 2009-05-14 | 2012-06-07 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
| CN102711472B (en) * | 2009-07-02 | 2015-12-02 | 江苏康缘药业股份有限公司 | Phosphorous quinazoline compound and using method thereof |
| SI2451445T1 (en) | 2009-07-06 | 2019-07-31 | Boehringer Ingelheim International Gmbh | Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient |
| JP2013512882A (en) | 2009-12-07 | 2013-04-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | BIBW2992 for use in the treatment of triple negative breast cancer |
| US20120107304A1 (en) * | 2010-04-27 | 2012-05-03 | Boehringer Ingelheim International Gmbh | Combination therapy in treatment of oncological and fibrotic diseases |
| PL2608792T3 (en) | 2010-08-26 | 2018-03-30 | Boehringer Ingelheim International Gmbh | Methods of administering an egfr inhibitor |
| US9012464B2 (en) | 2010-11-25 | 2015-04-21 | Ratiopharm Gmbh | Salts and polymorphic forms of Afatinib |
| KR20200003933A (en) | 2011-03-04 | 2020-01-10 | 뉴젠 세러퓨틱스 인코포레이티드 | Alkyne substituted quinazoline compound and methods of use |
| CN102731485B (en) * | 2011-04-02 | 2016-06-15 | 齐鲁制药有限公司 | 4-(substituted benzene amino) quinazoline derivant and preparation method thereof, pharmaceutical composition and purposes |
| CN102918029B (en) * | 2011-05-17 | 2015-06-17 | 江苏康缘药业股份有限公司 | 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof |
| US8828391B2 (en) | 2011-05-17 | 2014-09-09 | Boehringer Ingelheim International Gmbh | Method for EGFR directed combination treatment of non-small cell lung cancer |
| CN102838590B (en) * | 2011-06-21 | 2014-07-09 | 苏州迈泰生物技术有限公司 | Amino quinazoline derivative and application thereof in preparation of antineoplastic drugs |
| US20170079444A1 (en) * | 2011-09-22 | 2017-03-23 | Future Foam, Inc. | Enhanced washable mattress topper |
| WO2013052157A1 (en) | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN103073539B (en) * | 2011-10-26 | 2016-05-11 | 齐鲁制药有限公司 | 4-(substituted benzene amino) quinazoline derivant and preparation method thereof, pharmaceutical composition and purposes |
| EP2875020B1 (en) | 2012-07-19 | 2017-09-06 | Boehringer Ingelheim International GmbH | Process for the preparation of a fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy- chinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one |
| EP2951171A1 (en) | 2013-02-01 | 2015-12-09 | Boehringer Ingelheim International GmbH | Radiolabeled quinazoline derivatives |
| CN103254156B (en) * | 2013-05-10 | 2015-08-26 | 苏州明锐医药科技有限公司 | Ah method is for the preparation method of Buddhist nun's intermediate |
| WO2014180271A1 (en) * | 2013-05-10 | 2014-11-13 | 苏州明锐医药科技有限公司 | Method for preparing afatinib and intermediate thereof |
| CN103288808B (en) * | 2013-05-16 | 2015-11-11 | 苏州明锐医药科技有限公司 | A kind of Ah method is for the preparation method of Buddhist nun |
| CN103242303B (en) * | 2013-05-16 | 2015-03-25 | 苏州明锐医药科技有限公司 | Afatinib preparation method |
| CN104540820B (en) * | 2013-07-16 | 2016-12-21 | 杭州普晒医药科技有限公司 | Afatinib acid-addition salts and crystal formation, its preparation method and pharmaceutical composition |
| CN104513229A (en) * | 2013-09-28 | 2015-04-15 | 正大天晴药业集团股份有限公司 | Quinazoline derivatives and preparation method thereof |
| CN104710413B (en) * | 2013-12-16 | 2019-05-03 | 江苏豪森药业集团有限公司 | The preparation method of two maleic acid Afatinibs |
| CN104744445A (en) * | 2013-12-30 | 2015-07-01 | 广东东阳光药业有限公司 | Crystal form of tyrosine kinase inhibitor |
| US9242965B2 (en) | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
| WO2015103456A1 (en) * | 2014-01-02 | 2015-07-09 | Teva Pharmaceuticals International Gmbh | Crystalline forms of afatinib di-maleate |
| CN104803992A (en) * | 2014-01-25 | 2015-07-29 | 广东东阳光药业有限公司 | Crystal form of Afatinib dimaleate |
| WO2016001844A1 (en) * | 2014-06-30 | 2016-01-07 | Sun Pharmaceutical Industries Limited | Amorphous form of afatinib dimaleate |
| CN105315263B (en) * | 2014-07-30 | 2018-11-27 | 正大天晴药业集团股份有限公司 | The synthetic method of afatinib intermediate |
| WO2016027243A1 (en) * | 2014-08-21 | 2016-02-25 | Dr. Reddy’S Laboratories Limited | Novel solid state forms of afatinib dimaleate |
| WO2016051380A1 (en) * | 2014-10-01 | 2016-04-07 | Sun Pharmaceutical Industries Limited | Crystalline form of afatinib dimaleate |
| CN105534920B (en) * | 2014-10-29 | 2020-07-10 | 江苏豪森药业集团有限公司 | Pharmaceutical composition and preparation method thereof |
| CN104402872B (en) * | 2014-11-14 | 2016-08-24 | 广东东阳光药业有限公司 | A kind of crystallization impurity-removing method |
| CN104447713B (en) * | 2014-11-18 | 2019-03-29 | 江苏奥赛康药业股份有限公司 | The preparation method of afatinib compound |
| EP3023421A1 (en) | 2014-11-21 | 2016-05-25 | Sandoz Ag | Crystalline forms of afatinib dimaleate |
| CN104529800B (en) * | 2014-12-08 | 2017-01-25 | 重庆威鹏药业有限公司 | Preparation method of trans-4-dimethylaminocrotonic acid and its salt |
| CN105801567A (en) * | 2014-12-31 | 2016-07-27 | 徐州万邦金桥制药有限公司 | Purifying method of afatinib dimaleate |
| CN105801568B (en) * | 2015-01-15 | 2019-07-30 | 杭州普晒医药科技有限公司 | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition |
| RU2720810C2 (en) | 2015-03-20 | 2020-05-13 | Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. | Salts of a quinazoline derivative and a method for production thereof |
| US10329281B2 (en) | 2015-04-17 | 2019-06-25 | Hetero Labs Ltd | Polymorphs and process for the preparation of quinazolinyl derivatives |
| CN105859641B (en) * | 2015-05-05 | 2018-11-16 | 杭州华东医药集团新药研究院有限公司 | The crystal and its preparation method and application of quinazoline crotonyl compounds 2-maleate |
| CN104892584B (en) * | 2015-05-27 | 2018-03-23 | 重庆泰濠制药有限公司 | Double maleate unformed shapes of a kind of Afatinib and preparation method thereof, preparation |
| CN107980041A (en) | 2015-06-12 | 2018-05-01 | 费森尤斯卡比肿瘤学有限公司 | The polymorphic forms of Afatinib free alkali and its dimaleate |
| CN104926800A (en) * | 2015-06-26 | 2015-09-23 | 河北神威药业有限公司 | Crystal form of afatinib di-meleate and method for preparing crystal form |
| CN105175331B (en) * | 2015-08-14 | 2019-04-26 | 江苏苏中药业集团股份有限公司 | A kind of preparation method of the molecular targeted anti-tumor drug of EGFR class |
| US10525059B2 (en) | 2015-08-21 | 2020-01-07 | Fresenius Kabi Oncology, Ltd. | Pharmaceutical compositions comprising Afatinib |
| WO2017093789A1 (en) * | 2015-12-03 | 2017-06-08 | Mylan Laboratories Ltd. | Polymorphic forms of afatinib dimaleate |
| CN106831733B (en) * | 2015-12-07 | 2021-05-11 | 海南先声药业有限公司 | Preparation method and application of afatinib cis-isomer |
| CN106866641A (en) * | 2015-12-11 | 2017-06-20 | 河北神威药业有限公司 | A kind of process for purification of Afatinib |
| CN108430990B (en) | 2015-12-25 | 2020-08-25 | 山东轩竹医药科技有限公司 | Crystal of quinazoline derivative and method for producing same |
| CN106916147A (en) * | 2015-12-25 | 2017-07-04 | 中美华世通生物医药科技（武汉）有限公司 | Compound and its production and use |
| CN105669658B (en) * | 2016-04-05 | 2018-06-29 | 北京民康百草医药科技有限公司 | A kind of process for purification of Afatinib |
| CN107488171B (en) * | 2016-06-10 | 2020-08-28 | 山东新时代药业有限公司 | Preparation method of afatinib |
| CN107488153B (en) * | 2016-06-10 | 2020-06-23 | 山东新时代药业有限公司 | Afatinib intermediate compound |
| CN107488172B (en) * | 2016-06-10 | 2020-06-12 | 山东新时代药业有限公司 | Preparation method of afatinib |
| CN107488194B (en) * | 2016-06-10 | 2021-07-30 | 山东新时代药业有限公司 | Afatinib intermediate and preparation method thereof |
| CN106243092B (en) * | 2016-07-28 | 2019-02-15 | 南京臣功制药股份有限公司 | A kind of highly selective method for preparing maleic acid Afatinib |
| MA46852A (en) | 2016-11-17 | 2019-09-25 | Univ Texas | COMPOUNDS WITH ANTITUMOR ACTIVITY AGAINST CANCER CELLS CARRIER OF EGFR OR HER2 MUTATIONS EXON 20 |
| TWI808958B (en) | 2017-01-25 | 2023-07-21 | 美商特普醫葯公司 | Combination therapy involving diaryl macrocyclic compounds |
| CN110461832A (en) | 2017-04-06 | 2019-11-15 | 庄信万丰股份有限公司 | The new model of Afatinib 2-maleate |
| CN108358900A (en) * | 2018-03-30 | 2018-08-03 | 东北制药集团股份有限公司 | A kind of preparation method of Afatinib and its maleate |
| KR20190141607A (en) | 2018-06-14 | 2019-12-24 | 주식회사 에이티파머 | Composition for anti-pancreatic cancer and anti-pancreatic adjuvant comprising alloferon |
| KR102257913B1 (en) | 2018-07-17 | 2021-05-28 | 주식회사 에이티파머 | Composition for treating pulmonary fibrosis comprising alloferon |
| CN109824657A (en) * | 2019-03-26 | 2019-05-31 | 石药集团中奇制药技术（石家庄）有限公司 | Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application |
| CN110563710B (en) * | 2019-09-21 | 2020-05-19 | 广东安诺药业股份有限公司 | Preparation method of afatinib maleate |
| CN110590754A (en) * | 2019-09-21 | 2019-12-20 | 广东安诺药业股份有限公司 | Preparation method of afatinib maleate intermediate |
| CN113121512B (en) * | 2019-12-30 | 2022-11-04 | 江苏晶立信医药科技有限公司 | Preparation method of quinazolinyl butene amide compound |
| KR20210106158A (en) | 2020-02-20 | 2021-08-30 | 서울대학교산학협력단 | Anti-cancer adjuvant comprising alloferon |
| KR20210106157A (en) | 2020-02-20 | 2021-08-30 | 서울대학교산학협력단 | Composition for anti-ovarian cancer and anti-cancer adjuvant comprising alloferon |
Family Cites Families (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8618846D0 (en) | 1986-08-01 | 1986-09-10 | Smithkline Beckman Corp | Chemical process |
| JPS6442472A (en) | 1987-08-10 | 1989-02-14 | Kanebo Ltd | Quinazoline derivative, production thereof and brain function disorder improving agent containing said derivative as active ingredient |
| GB9005014D0 (en) * | 1990-03-06 | 1990-05-02 | Janssen Pharmaceutica Nv | N.(4.piperidinyl)(dihydrobenzofuran or dihydro.2h.benzopyran)carboxamide derivatives |
| RU2043352C1 (en) * | 1991-07-01 | 1995-09-10 | Пермский фармацевтический институт | 2-propyl-3-(5-nitrofurfulydene)-amino-4(3h)-quinazoline showing antistaphylococcus and analgetic activities |
| AU661533B2 (en) | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
| GB9401182D0 (en) | 1994-01-21 | 1994-03-16 | Inst Of Cancer The Research | Antibodies to EGF receptor and their antitumour effect |
| EP2295415A1 (en) | 1995-03-30 | 2011-03-16 | OSI Pharmaceuticals, Inc. | Quinazoline derivatives |
| GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| SI9620103A (en) | 1995-07-06 | 1998-10-31 | Novartis Ag | Pyrrolopyrimidines and processes for the preparation thereof |
| PL190489B1 (en) | 1996-04-12 | 2005-12-30 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
| UA73073C2 (en) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Substituted 3-cyan chinolines |
| ZA986732B (en) * | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
| ZA986729B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
| TW436485B (en) | 1997-08-01 | 2001-05-28 | American Cyanamid Co | Substituted quinazoline derivatives |
| GB9800569D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
| US6297258B1 (en) * | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6262088B1 (en) | 1998-11-19 | 2001-07-17 | Berlex Laboratories, Inc. | Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants |
| ID29800A (en) * | 1999-02-27 | 2001-10-11 | Boehringer Ingelheim Pharma | 4-AMINO-KINAZOLIN AND KINOLIN DISTRICTS THAT HAVE INHIBITOR EFFECTS ON SIGNAL TRANSDUKSI MEDIUMED BY THYROSIN KINASE |
| DE19911366A1 (en) | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | New 4-amino-quinazoline or quinoline derivatives, are tyrosine kinase-mediated signal transduction inhibitors useful e.g. for treating tumors, polyps or respiratory or gastrointestinal diseases |
| DE19911509A1 (en) | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
| YU90901A (en) | 1999-06-21 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh. & Co.Kg. | Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof |
| US6627634B2 (en) * | 2000-04-08 | 2003-09-30 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them |
| US20030158196A1 (en) * | 2002-02-16 | 2003-08-21 | Boehringer Ingelheim Pharma Gmbh Co. Kg | Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors |
| US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
| DE10063435A1 (en) * | 2000-12-20 | 2002-07-04 | Boehringer Ingelheim Pharma | Chinazoline derivatives, pharmaceuticals containing these compounds, their use and process for their preparation |
| DE10204462A1 (en) * | 2002-02-05 | 2003-08-07 | Boehringer Ingelheim Pharma | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
| DE10221018A1 (en) * | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Use of inhibitors of EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy |
| US20030225079A1 (en) * | 2002-05-11 | 2003-12-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy |
| PE20040945A1 (en) * | 2003-02-05 | 2004-12-14 | Warner Lambert Co | PREPARATION OF SUBSTITUTED QUINAZOLINES |
| US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
| DE10349113A1 (en) | 2003-10-17 | 2005-05-12 | Boehringer Ingelheim Pharma | Process for the preparation of aminocrotonyl compounds |
| US20060058311A1 (en) * | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
| SI1948180T1 (en) | 2005-11-11 | 2013-06-28 | Boehringer Ingelheim International Gmbh | Combination treatment of cancer comprising egfr/her2 inhibitors |
| CA2833706C (en) * | 2005-11-11 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Quinazoline derivatives for the treatment of cancer diseases |
| JP5241513B2 (en) * | 2006-01-26 | 2013-07-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Method for the synthesis of aminocrotonylamino substituted quinazoline derivatives |
| MX2009002710A (en) | 2006-09-18 | 2009-03-25 | Boehringer Ingelheim Int | Method for treating cancer harboring egfr mutations. |
| US8022216B2 (en) | 2007-10-17 | 2011-09-20 | Wyeth Llc | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
| UY31867A (en) * | 2008-06-06 | 2010-01-29 | Boehringer Ingelheim Int | NEW SOLID PHARMACEUTICAL FORMULATIONS THAT INCLUDE BIBW 2992 |
| EP2387401A1 (en) * | 2009-01-14 | 2011-11-23 | Boehringer Ingelheim International GmbH | Method for treating colorectal cancer |
| SI2451445T1 (en) * | 2009-07-06 | 2019-07-31 | Boehringer Ingelheim International Gmbh | Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient |
| JP2013512882A (en) | 2009-12-07 | 2013-04-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | BIBW2992 for use in the treatment of triple negative breast cancer |
| US9012464B2 (en) | 2010-11-25 | 2015-04-21 | Ratiopharm Gmbh | Salts and polymorphic forms of Afatinib |
| WO2013052157A1 (en) | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN104540820B (en) | 2013-07-16 | 2016-12-21 | 杭州普晒医药科技有限公司 | Afatinib acid-addition salts and crystal formation, its preparation method and pharmaceutical composition |
| WO2016027243A1 (en) | 2014-08-21 | 2016-02-25 | Dr. Reddy’S Laboratories Limited | Novel solid state forms of afatinib dimaleate |
| CN104892584B (en) | 2015-05-27 | 2018-03-23 | 重庆泰濠制药有限公司 | Double maleate unformed shapes of a kind of Afatinib and preparation method thereof, preparation |
| CN104926800A (en) | 2015-06-26 | 2015-09-23 | 河北神威药业有限公司 | Crystal form of afatinib di-meleate and method for preparing crystal form |
-
2003
- 2003-10-17 DE DE10349113A patent/DE10349113A1/en not_active Withdrawn
-
2004
- 2004-09-15 US US10/941,116 patent/US20050085495A1/en not_active Abandoned
- 2004-10-12 CN CN2004800305555A patent/CN1867564B/en active Active
- 2004-10-12 BR BR122013033343A patent/BR122013033343B8/en active IP Right Grant
- 2004-10-12 EA EA200600604A patent/EA016624B1/en active Protection Beyond IP Right Term
- 2004-10-12 RS RS20060260A patent/RS53398B/en unknown
- 2004-10-12 PT PT47659271T patent/PT1678165E/en unknown
- 2004-10-12 RS RS20130524A patent/RS60563B1/en unknown
- 2004-10-12 PL PL04765927T patent/PL1678165T3/en unknown
- 2004-10-12 AU AU2004281938A patent/AU2004281938B2/en active Active
- 2004-10-12 KR KR1020127003787A patent/KR101282812B1/en active Protection Beyond IP Right Term
- 2004-10-12 UA UAA200605327A patent/UA91006C2/en unknown
- 2004-10-12 SG SG200800279-2A patent/SG139743A1/en unknown
- 2004-10-12 KR KR1020067009605A patent/KR101180752B1/en active Protection Beyond IP Right Term
- 2004-10-12 SI SI200432099T patent/SI1678165T1/en unknown
- 2004-10-12 NZ NZ547154A patent/NZ547154A/en unknown
- 2004-10-12 JP JP2006534662A patent/JP4594317B2/en active Active
- 2004-10-12 PT PT121556625T patent/PT2508521E/en unknown
- 2004-10-12 ES ES04765927.1T patent/ES2440466T3/en active Active
- 2004-10-12 EP EP12155662.5A patent/EP2508521B2/en active Active
- 2004-10-12 PL PL12155662.5T patent/PL2508521T5/en unknown
- 2004-10-12 ES ES12155662T patent/ES2563211T5/en active Active
- 2004-10-12 CA CA2759063A patent/CA2759063C/en active Active
- 2004-10-12 EP EP04765927.1A patent/EP1678165B1/en active Active
- 2004-10-12 DK DK04765927.1T patent/DK1678165T3/en active
- 2004-10-12 MX MX2011004537A patent/MX338920B/en unknown
- 2004-10-12 DK DK12155662.5T patent/DK2508521T4/en active
- 2004-10-12 HU HUE12155662A patent/HUE028254T2/en unknown
- 2004-10-12 UA UAA200810609A patent/UA91401C2/en unknown
- 2004-10-12 RS YUP-2006/0260A patent/RS20060260A/en unknown
- 2004-10-12 SI SI200432301T patent/SI2508521T2/en unknown
- 2004-10-12 NZ NZ583049A patent/NZ583049A/en unknown
- 2004-10-12 CA CA2541928A patent/CA2541928C/en active Active
- 2004-10-12 WO PCT/EP2004/011378 patent/WO2005037824A2/en active Application Filing
- 2004-10-12 HR HRP20160246TT patent/HRP20160246T4/en unknown
- 2004-10-12 ME MEP-2008-508A patent/ME00341B/en unknown
- 2004-10-12 BR BRPI0415424A patent/BRPI0415424B8/en active IP Right Grant
- 2004-10-12 MX MXPA06004076A patent/MXPA06004076A/en active IP Right Grant
- 2004-10-12 CN CNA2008101664841A patent/CN101402631A/en active Pending
- 2004-10-14 MY MYPI2010002645A patent/MY155425A/en unknown
- 2004-10-14 MY MYPI20044237A patent/MY149921A/en unknown
- 2004-10-14 UY UY28559A patent/UY28559A1/en active IP Right Grant
- 2004-10-15 TW TW093131395A patent/TWI348468B/en active
- 2004-10-15 PE PE2004001000A patent/PE20050965A1/en active IP Right Grant
- 2004-10-15 PE PE2010000135A patent/PE20100267A1/en not_active Application Discontinuation
- 2004-10-15 AR ARP040103754A patent/AR046118A1/en not_active Application Discontinuation
- 2004-10-15 TW TW099147116A patent/TWI373470B/en active
-
2006
- 2006-03-16 ZA ZA200602234A patent/ZA200602234B/en unknown
- 2006-04-11 IL IL174951A patent/IL174951A/en active IP Right Grant
- 2006-04-17 EC EC2006006509A patent/ECSP066509A/en unknown
- 2006-05-15 NO NO20062181A patent/NO333971B1/en unknown
- 2006-07-14 US US11/457,622 patent/US8426586B2/en active Active
-
2007
- 2007-03-19 HK HK07102938.4A patent/HK1095817A1/en unknown
-
2010
- 2010-06-21 JP JP2010140697A patent/JP5264830B2/en active Active
-
2011
- 2011-03-16 AU AU2011201171A patent/AU2011201171B2/en active Active
- 2011-11-10 IL IL216249A patent/IL216249A/en active IP Right Grant
-
2013
- 2013-05-10 NO NO20130663A patent/NO335103B1/en unknown
- 2013-12-09 CY CY20131101112T patent/CY1114866T1/en unknown
- 2013-12-20 HR HRP20131214TT patent/HRP20131214T1/en unknown
-
2015
- 2015-02-04 UY UY0001035979A patent/UY35979A/en active IP Right Grant
-
2016
- 2016-03-11 CY CY20161100212T patent/CY1117279T1/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2563211T5 (en) | Procedure for the preparation of aminocrotonyl compounds | |
| ES2772498T3 (en) | Preparation of a mek inhibitor and formulation comprising the same | |
| ES2382806T3 (en) | Cyclohexanecarboxylic acid compound | |
| ES2879294T3 (en) | Polymorphic forms of Belinostat and processes for their preparation | |
| JP6374436B2 (en) | Pure erlotinib | |
| PT726899E (en) | NEW PYRAZINOCARBOXAMIDE DERIVATIVES ITS PREPARATION AND ITS USE IN MEDICINES | |
| ES2699884T3 (en) | New crystalline compound of arylalkylamine and method to produce the same | |
| ES2815924T3 (en) | Highly stable crystalline form D1 of the monoethanolamine salt of eltrombopag | |
| ES2334221T3 (en) | A METHOD TO PRODUCE 1- (2- (BENZIMIDAZOL-2-ILTIO) ETIL) PIPERAZINE OR ITS SALT. | |
| CA2628026A1 (en) | Diazonamide a analog |